ESPEYB25 6. DSD and Gender Incongruence Gender Incongruence: Immune System Adaptation during Gender-Affirming Testosterone Treatment (2 abstracts)
6.14. Immune system adaptation during gender-affirming testosterone treatment
Lakshmikanth T , Consiglio C , Sardh F , Forlin R , Wang J , Tan Z , Barcenilla H , Rodriguez L , Sugrue J , Noori P , Ivanchenko M , Piñero Páez L , Gonzalez L , Habimana Mugabo C , Johnsson A , Ryberg H , Hallgren Æ , Pou C , Chen Y , Mikeš J , James A , Dahlqvist P , Wahlberg J , Hagelin A , Holmberg M , Degerblad M , Isaksson M , Duffy D , Kämpe O , Landegren N & Brodin P
Nature. 2024 Sep;633(8028):155-164. doi: 10.1038/s41586-024-07789-z
Erratum in: Nature. 2024 Oct;634(8033):E5. doi: 10.1038/s41586-024-08081-w
Brief summary: This study examined changes in the immune system in 23 adult transgender men (female sex registered at birth) during the first year of testosterone treatment. Bulk mRNA sequencing of whole blood showed downregulation of hallmark interferon alpha responses and upregulation of tumour necrosis factor signalling through NFkappaB and Hallmark inflammatory responses. These changes were related to changes in the number and function of plasmacytoid dendritic cells, monocytes and natural killer cells. Analysis of existing datasets on immune responses in cisgender males and females supported the role of sex hormones in regulation of the IFN-I/TNF axis.
The study helps to tease apart the contribution of hormonal as opposed to genetic and behavioural factors to sex differences in the immune system, and in infectious, inflammatory and auto-immune conditions. The finding that testosterone alters the IFN-1/TNF axis, as previously reported (1), with an increased pro-inflammatory response, may explain the higher risk of cytokine storm and increased mortality from severe infections among men from the general population.
For transgender men, the results suggest that testosterone treatment may increase the risk of severe infections. One Turkish questionnaire-based study among 179 transgender men and 59 transgender women found that transgender men on testosterone were 3.46 times more likely than transgender women on estrogen to have contracted COVID-19 vs a 1.01 ratio of women to men in the general Turkish population (2). However, most reported a mild course of the disease with none admitted to the intensive care. A previous study from the Netherlands reported no deaths from infectious diseases among 1641 transgender men who had started testosterone treatment at a median age of 23 years (IQR 20-32), but given the follow-up time of median 5 years (IQR 2-17) this was still a relatively young population (3).
Another recent study reported that testosterone affected CD4+ T-cell function in transgender men which might be relevant for the risk of auto-immune conditions (4) and a registry-based study reported prescription of gender affirming hormone treatment was associated with an increased incidence rate of auto-immune disease in transgender men (5). Future studies will have to confirm if and how testosterone treatment alters morbidity and mortality from infections and auto-immune diseases in transgender men.
References: 1. Grünhagel B, Borggrewe M, Hagen SH, Ziegler SM, Henseling F, Glau L, Thiele RJ, Pujantell M, Sivayoganathan V, Padoan B, Claussen JM, Düsedau A, Hennesen J, Bunders MJ, Bonn S, Tolosa E, Krebs CF, Dorn C, Altfeld M. Reduction of IFN-I responses by plasmacytoid dendritic cells in a longitudinal trans men cohort. iScience. 2023 Oct 13;26(11):108209. PMID: 37953956.2. Durcan E, Turan S, Bircan BE, Yaylamaz S, Demirel O, Demir AN, Sulu C, Kara Z, Sahin S, Taze SS, MefkureOzkaya H, Kadioglu P. TransCOVID: Does Gender-Affirming Hormone Therapy Play a Role in Contracting COVID-19? J Sex Marital Ther. 2022;48(4):415-426. PMID: 34806552.3. de Blok CJ, Wiepjes CM, van Velzen DM, Staphorsius AS, Nota NM, Gooren LJ, Kreukels BP, den Heijer M. Mortality trends over five decades in adult transgender people receiving hormone treatment: a report from the Amsterdam cohort of gender dysphoria. Lancet Diabetes Endocrinol. 2021 Oct;9(10):663-670. PMID: 34481559.4. Henze L, Will N, Lee D, Haas V, Casar C, Meyer J, Stein S, Mangler F, Steinmann S, Poch T, Krause J, Fuss J, Schröder J, Kulle AE, Holterhus PM, Bonn S, Altfeld M, Huber S, Lohse AW, Schwinge D, Schramm C. Testosterone affects female CD4+ T cells in healthy individuals and autoimmune liver diseases. JCI Insight. 2025 Apr 22;10(8):e184544. PMID: 40260919.5. Glintborg D, Møller JK, Rubin KH, Christensen LL, Andersen MS. Autoimmune diseases in 3812 Danish transgender persons and 38 120 cisgender controls before and after transgender care: a register-based cohort study. Eur J Endocrinol. 2025 Mar 27;192(4):408-417. PMID: 40086810.
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